Venigalla, R.K.C., McGuire, V.A., Clarke, R., Patterson-Kane, J.C., Najafov, A., Toth, R., McCarthy, P.C., Simeons, F., Stojanovski, L. and Arthur, J.S.C. (2013) PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development. EMBO Journal, 32(7), pp. 1008-1022. (doi: 10.1038/emboj.2013.40)
Full text not currently available from Enlighten.
Abstract
Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Patterson-Kane, Professor Janet |
| Authors: | Venigalla, R.K.C., McGuire, V.A., Clarke, R., Patterson-Kane, J.C., Najafov, A., Toth, R., McCarthy, P.C., Simeons, F., Stojanovski, L., and Arthur, J.S.C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | EMBO Journal |
| Publisher: | Nature |
| ISSN: | 0261-4189 |
| ISSN (Online): | 1460-2075 |
| Published Online: | 05 March 2013 |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric